Osteoporosis is considered to be one of the most debilitating diseases of the adult population in the industrialized nations. Osteoporosis is the general term used for diseases of diverse etiology that are characterized by a reduction in the mass of bone per unit volume to a level below that required for adequate mechanical support (Krane, S. M., et al., "Metabolic Bone Disease," in Harrison's Principles of Internal Medicine, pg. 1889 edition 11 (1987)). One form of osteoporosis is senile osteoporosis which is responsible for a large portion of the health dollars spent on the geriatric population (Resnick, N. M., et al., "Senile Osteoporosis Reconsidered," JAMA 261:1025-1029 (1989)). The two other most common forms of osteoporosis are peri- or postmenopausal osteoporosis and corticosteroid induced osteoporosis. The most devastating consequence of osteoporosis is the occurrence of a pathologic fracture in trabecular bone, such as the vertebral spine or the hip. No current medical regimen is effective in fully preventing this common malady and no treatments are capable of reversing this affliction.
The pathophysiology of osteoporosis is poorly understood. It probably is related to an interplay of osteoblasts, osteoclasts, and other hormonally mediated events that alter calcium homeostasis. Most current treatment strategies attempt to reduce the bone loss of calcium in order to retard the onset of osteoporosis (Dawon-Hughes, B. et al., "A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women," NEJM 323:878-83 (1990)); Storm, T. et al., "Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis," NEJM 322:1264-1271 (1990)). Attempts to produce new and structurally functional bone have not been successful (Riggs, B. L. et al., "Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis," NEJM 322:802-809 (1990)).
Retinoids are currently approved by the FDA for use in the treatment of cystic acne and psoriasis vulgaris. However, they have also been used in the treatment of Darier's disease, pityriasis ruba pilaris, and basal cell nevus syndrome (Ellis, C. N. et al., "Etretinate therapy," JAAD 16:267-291 (1987); Leyden J. J. "Retinoid and acne," JAAD 19:267-291 (1988)). Bone discomfort occurs in a significant number of patients receiving these medications. Studies have demonstrated that ligaments and tendons of patients receiving retinoids may become calcified but that the bones of some of these patients may demonstrate osteopenia or the radiographic appearance that the bones are losing calcium (McGuire J. et al., "Skeletal changes associated with chronic isotretinoin and etretinate administration," Dermatologica 173:169-181 (1987)). The first study that has attempt to demonstrate an alteration in bone mineralization in patients on retinoids was unable to demonstrate any change in the bone mineral content in long bones (Torok, L. et al., "Bone scintigraphic examinations in patients treated with retinoid a prospective study," Br J Derm 120:31-36 (1989)). Animal studies have demonstrated that retinoids stimulate the bone remodeling cells (Teelman, K., "Retinoids toxicology and teratogenicity to date," Pharmac Ther 40:29-43 (1989)). Studies on osteoclasts have also demonstrated that retinoids appear to stimulate cellular activity (Trechsel U. et al., "Hypocalcemia induced with an arotinoid in thyroparathyroidectomized rats," J Clin Invest 80:1679-1686 (1987)).
Descriptions of the effects of retinoids, which are synthetic analogues of vitamin A, on bone have been confusing. Studies have noted calcification of ligaments and tendons, vertebral hyperostosis, periosteal thickening, and osteopenia (Melnick, B. et al., "Retrospective radiographic study of skeletal changes after long-term tretinate therapy," Br J. Dermatol 116:207-212 (1987); McGuire J., et al., "Skeletal changes associated with chronic isotretinoin and etretinate administration," Dermatol 175:169-81 (1987); Torok L. et al. "Bone-scintigraphic examinations in patients treated with retinoids: a prospective study," Br J Dermatol 120:31-36 (1989)). Studies have shown that retinoids can cause the synthesis of cellular products from cells of similar embryonic origin as bone forming cells (Ellis, C. et al., "Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin," F. Supp. JAAD 23:629-637 (1990)).
Surprisingly in view of the literature on retinoids described herein, it has been demonstrated by the Applicant that retinoids can reverse the bone mineral loss that occurs in mammals with osteoporosis. It has also been observed that the gain in bone mineral loss appears to be functionally sound and prevents the occurrence of pathologic fractures.